RelA/MicroRNA-30a/NLRP3 signal axis is involved in rheumatoid arthritis via regulating NLRP3 inflammasome in macrophages.
RelA/MicroRNA-30a/NLRP3 signal axis is involved in rheumatoid arthritis via regulating NLRP3 inflammasome in macrophages.
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DOI：
10.1038/s41419-021-04349-5
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发表时间：
2021-11-08
影响因子：
9
通讯作者：
Sun W
中科院分区：
文献类型：
--
作者：
Yang Q;Zhao W;Chen Y;Chen Y;Shi J;Qin R;Wang H;Wang R;Yuan H;Sun W
NLRP 3炎性小体在类风湿关节炎（RA）的发病机制中起重要作用。然而，滑膜巨噬细胞中miRNA对NLRP 3表达的转录后调控仍不清楚。本研究的目的是阐明RA的机制，重点是miRNA介导的NLRP 3炎性体的转录后调控。在这里，我们使用NLRP 3缺陷小鼠（NLRP 3 KO）与TNFα转基因小鼠（TNFTG）杂交，产生NLRP 3 KO/TNFTG小鼠，并在5月龄时将其关节表型与TNFTG和野生型（WT）同窝仔的关节表型进行比较。与WT小鼠相比，TNFTG小鼠关节骨体积和软骨面积减少，而炎症面积、侵蚀表面、ALP+成骨细胞数量、TRAP+破骨细胞数量以及RelA+F4/80+、Caspase-1+F4/80+、IL-1β+F4/80+滑膜细胞的面积增加。敲除NLRP 3可改善TNFTG小鼠的关节炎症和骨损伤此外，在TNFα引发的BMDM中，RelA正调控NLRP 3表达，但负调控miR-30 a。此外，miR-30 a通过直接结合其3 ′ UTR负性介导NLRP 3表达，表明miR-30 a介导的前馈环作用于NLRP 3。最后，关节内注射AAV-miR-30 a抑制TNFTG小鼠中的NLRP 3炎性体活化，减少关节炎症，并减轻骨损伤。因此，RelA/miR-30 a/NLRP 3信号轴通过调节巨噬细胞中的NLRP 3炎症体参与RA的发生。
NLRP3 inflammasome plays an important role in the pathogenesis of rheumatoid arthritis (RA). However, the post-transcriptional regulation of NLRP3 expression by miRNA in synovial macrophages is still not well understood. The aim of the study is to elucidate the mechanisms of RA with the focus on miRNAs mediated post-transcriptional regulation of the NLRP3 inflammasome. Here, we used NLRP3-deficient mice (NLRP3KO) to cross with TNFα-transgenic mice (TNFTG) to generate NLRP3KO/TNFTG mice, and compared their joint phenotypes with those of their TNFTG and wild-type (WT) littermates at 5 months of age. In comparison to WT mice, articular bone volume and cartilage area are decreased, whereas inflammed area, eroded surface, ALP+ osteoblast number, TRAP+ osteoclast number, and the areas of RelA+F4/80+, Caspase-1+F4/80+, IL-1β+F4/80+ synoviocytes are increased in the TNFTG mice. Knockout of NLRP3 ameliorates joint inflammation and bone damage in TNFTG mice. Further, in TNFα-primed BMDMs, RelA positively regulates NLRP3 expression, but negatively regulates miR-30a. Additionally, miR-30a negatively mediates NLRP3 expression by directly binding to its 3ʹ UTR, suggesting a miR-30a-mediated feedforward loop acting on NLRP3. Finally, intra-articular injection of AAV-miR-30a inhibits NLRP3 inflammasome activation, reduces joint inflammation, and attenuates bone damage in TNFTG mice. Thus, RelA/miR-30a/NLRP3 signal axis is involved in RA through regulating NLRP3 Inflammasome in macrophages.
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影响因子：
64.5
作者：
Kleaveland B;Shi CY;Stefano J;Bartel DP
通讯作者：
Bartel DP
香草酸通过抑制 NLRP3 炎症小体相关滑膜炎减少膝骨关节炎大鼠的疼痛相关行为
影响因子：
5.6
作者：
Ma Z;Huang Z;Zhang L;Li X;Xu B;Xiao Y;Shi X;Zhang H;Liao T;Wang P
通讯作者：
Wang P
影响因子：
4.9
作者：
Choulaki C;Papadaki G;Repa A;Kampouraki E;Kambas K;Ritis K;Bertsias G;Boumpas DT;Sidiropoulos P
通讯作者：
Sidiropoulos P
影响因子：
11.4
作者：
KEFFER, J;PROBERT, L;KOLLIAS, G
通讯作者：
KOLLIAS, G
影响因子：
6.2
作者：
McCall, Samuel H.;Sahraci, Mahnaz;Marriott, Ian
通讯作者：
Marriott, Ian